The present invention relates to novel and stable 1-(alkoxy or aroxy)carbonyl esters of diflunisal, i.e., 2-hydroxy-5-(2,4-difluorophenyl)benzoic acid and related compounds characterized as being:
(1) readily bioavailable;
(2) stable in aqueous formulation;
(3) non-irritant to mucous membranes of mouth, throat, and stomach when administered, and
(4) having long duration.
Diflunisal and its analogs are known analgesic and anti-inflammatory agents of high potency, long duration but low gastric irritation. It is disclosed in U.S. Pat. No. 3,714,226 issued Jan. 30, 1973 to William V. Ruyle et al. However, it has been found that because of its inherent property as a phenolic free acid, diflunisal is irritant to mucous membranes and is therefore unsuitable for oral aqueous or suppository formulations. Particularly, in long term chronic dosing, the irritancy of diflunisal especially its aqueous suspension may have undesirable effects on the histology of the mucous membranes, e.g., mucosa of mouth and throat. On the other hand, aqueous suspensions of the novel esters of this invention are devoid of the irritancy and can be administered to infants, the very old, or chronic patients having difficulty in swallowing tablets, capsules or other forms of oral dose. Furthermore, it should be noted that the novel esters of this invention are stable in vitro at physiological pH ranges (1.2-8) but are readily cleaved during absorption by the mucous membranes. The products of cleavage from the ester, i.e., carbon dioxide, acetaldehyde and alcohols are advantageously physiologic in nature.
Another aspect of the present invention involves the improved solubility range of the novel alkoxycarbonylalkyl esters which are slightly less soluble in water but more soluble in organic solvents, e.g., 1,3-butenediol, mono- or diglycerides, than diflunisal. This improved solubility facilitates the preparation of aqueous or oleaginous formulations for parenteral injections.
Accordingly, it is an object of the present invention to provide novel and stable 1-(alkoxy or aroxy)carbonyloxyalkyl esters of diflunisal and related compounds particularly suitable for aqueous oral or suppository formulations.
Another object of the present invention is to provide processes for the preparation of these novel esters.
Still another object of the present invention is to provide a pharmaceutical composition particularly suitable for parenteral, oral and/or, suppository formulation comprising a pharmaceutically acceptable carrier and an effective amount of the novel esters for the treatment of pain, fever and inflammation.
Finally, it is the ultimate object of the present invention to provide a method of treating inflammation, pain and fever comprising the administration of an effective amount of the novel esters or a pharmaceutical composition thereof to a mammal in need of such treatment.